This is an open label, single centre, phase II study of neoadjuvant drug treatment with dabrafenib + trametinib in patients with resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 mutation positive melanoma.

The main aim of this study is to find out if giving of a new combined drug treatment to patients with melanoma that has spread to the lymph nodes BEFORE they have surgery, will result in improved clinical and pathological response of the melanoma tissue after 12 weeks treatment.

Number of episodes (and patient number) of infection at wound site requiring intravenous antibiotics and wound drainage, duration of time from surgery to removal of drain because of ceased or minimal drainage, number of episodes (and patient number) of seroma formation at wound site requiring any intervention and volume of seroma drainage, number of episodes (and patient number) of bleeding .from wound requiring return to theatre or transfusion(s), bioimpedance measures of limb distal to site of CLND (axilla and groin only) at baseline, and weeks 8, 24 and 40 after CLND (20, 40 and 52 weeks after starting study treatment) and correlation of surgical outcomes with response to study treatment.

Immune tumour tissue will be assessed as outlined in 3b and 3c. Peripheral blood will be examined for levels of cytokines and chemokines (Millipore multiplex) and changes in host immune response in tumour and peripheral blood will be correlated with pathological and clinical response.

Measurement of the following, at regular intervals in all patients, with or without pyrexia, and at every febrile episode: serum chemokines and cytokines, including IL-1, IL6, IL-8, IL-10, IL-18, PD1, gamma interferon and TNF-alpha; plasma and serum parent and metabolite concentrations, white blood cell subsets, liver function tests; AST, ALT, Bilirubin, full blood count, other changes such as cortisol, adrenocorticotropic hormone.

Relapse free survival [ Time Frame: 52 weeks plus the time when 70% of patients have died ] [ Designated as safety issue: No ]

Relapse free survival defined as the interval from commencement of study treatment to local or distant recurrence with censoring of patients dying from causes other than melanoma or treatment related toxicity at date of death. Patients alive without recurrence or with second primary cancers will be censored at date of last assessment. A second primary melanoma will not be considered relapse.

Overall survival [ Time Frame: 52 weeks plus until the time that 70% of patients have died ] [ Designated as safety issue: No ]

Overall survival defined as the interval from commencement of study treatment to the date of death. Patients still alive will be censored at the date of last follow up (until 70% of patients have died)

Patients will receive neoadjuvant treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 12 weeks. Patients will then have complete lymph node dissection and will continue on maintenance treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 40 weeks.

Other Name: GSK2118436

Drug: Trametinib

Patients will receive neoadjuvant treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 12 weeks. Patients will then have complete lymph node dissection and will continue on maintainance treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 40 weeks.

Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1

Adequate baseline organ function

Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment

Men with any female partner of childbearing potential must agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment

Exclusion Criteria:

Known mucosal or ocular melanoma or any unresectable in-transit metastases

Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to commencing study treatment.

Current or expected use of a prohibited medication(s)

Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)

Known HIV

A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

History of another malignancy or a concurrent malignancy except:

Patients who have been disease-free for 3 years and have a life expectancy of > 5 years;

Patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas.

A history or evidence of cardiovascular risk including any of the following: a. QT interval corrected for heart rate using the Bazett's formula ≥480 msec or ≥ 450 msec for patients with bundle branch block; b. History or evidence of current clinically significant uncontrolled arrhythmias; c. History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to commencement of study treatment; d. History or evidence of current ≥ Class II congestive heart failure; e. Abnormal cardiac valve morphology documented by echocardiogram which in the opinion of the investigator could interfere with the patient's safety.

A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

Any serious or unstable pre-existing medical conditions (aside from the malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the treating clinician, could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures.

Breastfeeding females

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01972347